Macitentan attenuates cardiovascular remodelling in infant rats with chronic lung disease

Journal of Translational Medicine

Philipp Baumann¹  Susanne Wiegert²  Francesco Greco²  Giovanni Pellegrini³  Vincenzo Cannizzaro⁴  Sven Wellmann⁵ 

[1] Department of Intensive Care Medicine and Neonatology, University Children’s Hospital Zurich, Zurich, Switzerland;Children’s Research Centre, University Children’s Hospital Zurich, Zurich, Switzerland;Department of Intensive Care Medicine and Neonatology, University Children’s Hospital Zurich, Zurich, Switzerland;Children’s Research Centre, University Children’s Hospital Zurich, Zurich, Switzerland;Zurich Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland;Laboratory for Animal Model Pathology (LAMP), Institute of Veterinary Pathology, University of Zurich, Zurich, Switzerland;Zurich Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland;Department of Neonatology, University Hospital Zurich, University of Zurich, Frauenklinikstrasse 10, 8091, Zurich, Switzerland;Zurich Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland;Department of Neonatology, University of Basel Children’s Hospital (UKBB), Basel, Switzerland;Department of Neonatology, University Children’s Hospital Regensburg (KUNO), University of Regensburg, Regensburg, Germany;

关键词: Chronic lung disease;    Endothelin receptor blockers;    Preterm;    Rats;    Infants;    Bronchopulmonary dysplasia;   

DOI  :  10.1186/s12967-022-03281-2

来源: Springer

【 摘 要 】

BackgroundCardiovascular impairment contributes to increased mortality in preterm infants with chronic lung disease. Macitentan, an endothelin-1 receptor antagonist, has the potential to attenuate pulmonary and cardiovascular remodelling.MethodsIn a prospective randomized placebo-controlled intervention trial, Sprague–Dawley rats were exposed to 0.21 or 1.0 fraction of inspired oxygen (FiO2) for 19 postnatal days. Rats were treated via gavage with placebo or macitentan from days of life 5 to 19. Alveoli, pulmonary vessels, α-smooth muscle actin content in pulmonary arterioles, size of cardiomyocytes, right to left ventricular wall diameter ratio, and endothelin-1 plasma concentrations were assessed.ResultsFiO2 1.0 induced typical features of chronic lung disease with significant alveolar enlargement (p = 0.012), alveolar (p = 0.048) and pulmonary vessel rarefaction (p = 0.024), higher α-smooth muscle actin content in pulmonary arterioles (p = 0.009), higher right to left ventricular wall diameter ratio (p = 0.02), and larger cardiomyocyte cross-sectional area (p < 0.001). Macitentan treatment significantly increased pulmonary vessel count (p = 0.004) and decreased right to left ventricular wall diameter ratios (p = 0.002). Endothelin-1 plasma concentrations were higher compared to placebo (p = 0.015). Alveolar number and size, α-smooth muscle actin, and the cardiomyocyte cross-sectional area remained unchanged (all p > 0.05).ConclusionThe endothelin-1 receptor antagonist macitentan attenuated cardiovascular remodelling in an infant rat model for preterm chronic lung disease. This study underscores the potential of macitentan to reduce cardiovascular morbidity in preterm infants with chronic lung disease.

【 授权许可】

CC BY